PROCESS FOR PREPARING SULPHONAMIDES

The present invention relates to a process for preparing a class of sulphonamides which are aspartyl protease inhibitors. These compounds find therapeutic use in the treatment of the human immunodeficiency virus (HIV). This virus is the causative agent for acquired immunodeficiency syndrome (AIDS). A number of anti-viral agents have been designed to target various steps in the replication cycle of HIV and one such approach involves aspartyl protease inhibitors. These compounds function by inhibiting the formation of viral protein precursors. One feature of known aspartyl protease inhibitors is that these compounds are generally complicated molecules which are difficult to prepare in a cost-effective and efficient manner. Frequently, multi-step syntheses, often involving a resolution step, are required to produce the end product.

A number of patents describe the preparation of compounds which are said to be effective against the human immunodeficiency virus. EP1194404 describes a novel class of sulphonamides which are aspartyl protease inhibitors as well as processes for producing such compounds. WO2005/000249 describes a structurally related group of sulphonamides which are also effective against the HIV aspartyl protease enzyme. WO2006/104646 describes another group of structurally related sulphonamides which are also active against the human immunodeficiency virus. Intermediates in the lengthy syntheses of compounds of this type are disclosed in the prior art in references such as EP0885887 and EP0715618.

In each case, the prior art processes suffer the disadvantage that a significant number of synthetic steps are required in order to produce the sulphonamide end product. Each synthetic step leads to both a reduction in yield and increases the possibility of competing side reactions. Thus, conventional routes require considerable effort to purify the product and may not give an optimal yield.

It is an aim of the present invention to provide a synthetically efficient process for the production of sulphonamide derivatives which avoids the problems of the prior art processes. One of the key reagents used in certain prior art routes is diazomethane. This material is both toxic and explosive and presents a considerable challenge to handle and use. Furthermore, special precautions must be taken during its use and it is not suitable for reactions which are to be performed on any significant scale. There is a further disadvantage that this material must be generated in situ under carefully controlled conditions each time the reagent is used. Another precursor used in the conventional routes involves reaction with a chiral amino-substituted epoxide which is effectively a masked amino acid fragment. This precursor is both expensive to produce and toxic. The present invention therefore aims to avoid the need to use expensive and/or harmful starting materials. It is also an aim of the present invention to provide a process in which the convergency (ie the bringing together of synthetic fragments) is maximised. It is thus an aim to provide a route to the sulphonamide compounds identified below which is able to offer potential improvements in yield relative to existing routes. It is a further aim of the process to reduce the number of synthetic steps required, and consequently to avoid the problem of competing reactions. The present invention also seeks to provide a more economical, cheaper route. There are advantages in waste management and environmental terms in utilising such a route. A further aim of the present invention is to provide a sulphonamide product with good enantiomeric purity. It is also an aim to ensure that the product contains as few impurities as possible.

We have now found an improved route to the sulphonamide derivatives of formula (I) identified below which overcomes many of the disadvantages of the prior art. The process of the present invention thus satisfies some or all of the above aims. The synthetic procedure of the present invention involves a convenient and efficient process utilising base coupling, decarboxylation and reduction steps to produce the desired compounds in good yield. One advantage of the process of the present invention is its convergent approach which leads to improved yields. The procedure also enables stereoselectivity to

be controlled to a high degree, thus avoiding the need for resolution procedures where chiral products are formed.

According to a first aspect of the present invention, there is a process for the preparation of a compound of formula (I)

(1)

by reduction of a compound of formula (II)

(H) wherein R ¹ is a protecting group; R ² is selected from the group comprising: hydrogen; C ₁ - ₁₀ alkyl; C ₁ - ₁₀ alkoxy; C ₂ -io alkenyl; C ₂ -io alkynyl; C ₁ - _I0 alkyl C _3-I0 cycloalkyl; and C _3-10 cycloalkyl; and R ³ , R ⁴ , R ⁵ , and R ⁶ are independently chosen substituents selected from the group comprising: hydrogen; C-|. _1O alkyl; Ci_ ₁₀ alkoxy; C ₂ - ₁₀ alkenyl; C _2-10 alkynyl; C _3-I0 cycloalkyl; aryl; -S-aryl, Ci_ ₁₀ alkylaryl; aryl Ci-ioalkyl; C _1-10 alkyl-X-C _1-10 alkyl where X is O, NH or S; het; CMD alkyl het; and het C _1- - _I0 alkyl; and

P is a protecting group or a group -SO ₂ R ⁷ where R ⁷ is selected from the group comprising: Ci _-10 alkyl; C _2-10 alkenyl; C _2-10 alkynyl; C ₃ - ₁₀ cycloalkyl; aryl; C _1-10 alkylaryl; aryl C^-malkyl; C _1- - _I0 alkyl-X-C^o alkyl where X is O, NH or S; het; C-i. ₁₀ alkyl het; and het C _1-10 alkyl;

wherein each of the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ , groups may be optionally independently substituted by from 1 to 5 groups independently selected from the group comprising: CF ₃ ; halo; NO ₂ ; CN; SH; OH; oxo; SR; OR; - NHR; -C(NH)NHR; -COOR; where in each case R is hydrogen or C _1-6 alkyl; and a group -O-(CH ₂ )f -O- wherein f is from 1 to 3 and said group is bound to two points of substitution on the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ substituents so as to form a ring fused to the substituent.

Preferably the reduction is an asymmetric reduction. In an embodiment, the reduction is performed with hydrogen or a source of hydride ions in the presence of a chiral catalyst.

In another aspect of the present invention there is provided a process for the preparation of a compound of formula (II)

(II) wherein P and R ¹ to R ⁷ are as previously defined in relation to the compound of formula (I), by decarboxylation of a compound of (III)

(III) wherein P and R ¹ to R ⁷ are as previously defined in relation to the compound of formula (I) and M is a Group IA or HA metal or M is an optionally substituted group selected from the group comprising: Ci_ ₁₀ alkyl, C _3- - _I0 cycloalkyl and aryl.

In an embodiment, the decarboxylation is performed in the presence of a proton source such as a mineral acid. Alternatively decarboxylation may be performed in the presence of an inorganic base. The decarboxylation step may be effected by the application of heat either with or without the presence of an acid or base. Preferebly, where M is not a metal, base hydrolysis is performed to remove the non-metal M group prior to decarboxylation.

In another aspect of the present invention there is provided a process for the preparation of a compound of formula (III)

(III)

wherein P and R ¹ to R ⁷ are as previously defined in relation to the compound of formula (I), by reaction of a compound of Formula (IV)

where R ¹ , R ³ , R ⁴ , and R ⁵ , are as defined in relation to Formula (I) and R ⁸ is a leaving group, with a compound of formula (V)

(V)

wherein P and R ² , R ⁶ and R ⁷ are as defined in Formula (I) and M is a Group IA or NA metal or M is an optionally substituted group selected from the group comprising: C-M ₀ alkyl, C3-10 cycloalkyl and aryl.

Compounds of formula (IV) are easily prepared by reaction of the corresponding alphahalo compound of formula (X)

wherein R ³ to R ⁵ and R ⁸ are as defined previously in relation to compounds of formula (IV) with a suitable carbamate using known methods.

Compounds of formulae (V) are available by literature methods.

In another aspect of the present invention, there is provided a process for the preparation of a compound of Formula (I):

the process comprising the steps:

(a) reacting a compound of formula (V):

R ² with a compound of formula (IV):

in the presence of a base to give a compound of Formula (III)

(b) decarboxylating the compound of Formula (III) to give a compound of Formula (II):

and

(c) reacting the compound of Formula (II) with a reducing agent under asymmetric hydrogenation conditions and optionally removing any protecting groups to give a compound of Formula (I), wherein R ¹ to R ⁸ , M and P are defined as above.

One feature of the present invention is the ability to control stereochemistry of the product to ensure a high degree of stereoselectivity or diastereoselectivity. Thus, according to a further aspect of the present invention there is provided a process for the preparation of a compound of Formula (IA):

or a process for the preparation of a compound of Formula (IB):

the process comprising the steps:

(a) reacting a compound of formula (V): with a compound of formula (IVA):

in the presence of a base to give a compound of Formula (IHA)

(b) decarboxylating the compound of Formula (I I IA) to give a compound of Formula (HA):

and

(c) reacting the compound of Formula (NA) with a reducing agent under asymmetric hydrogenation conditions and optionally removing any protecting groups to give a compound of Formula (IA) or (IB), wherein R ¹ to R ⁸ , M and P are as defined in relation to Formula (I).

In one embodiment of this aspect of the invention, the asymmetric conditions involve the use of a stereoselective reducing agent, more preferably stereoselective catalytic transfer hydrogenation.

In a particularly preferred embodiment, R ¹ is t-butyl, R ² is i-propyll, R ³ is phenyl, R ⁴ , R ⁵ and R ⁶ are all hydrogen, and P is SO ₂ C ₆ H ₄ NO ₂ . Preferably the reduction step involves a Rh catalyst based on a (R,S,S)-N-camphorsulphonyl-1 ,2- diphenylethylenediamine or a Ru catalyst of with (S,R,R)-N-camphorsulphonyl- 1,2-diphenylethylenediamine is employed.

In each of the Formulae (I) to (X) above, each of the substituents R ¹ to R ⁸ may be optionally substituted where chemically possible by from 1 to 5 groups independently chosen. More specifically, each of the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ , groups in those formulae may be optionally independently substituted by from 1 to 5 groups independently selected from the group comprising: CF ₃ ; halo; NO ₂ ; CN; SH; OH; oxo; SR*; OR*; -NHR*; -C(NH)NHR*; - COOR*; where in each case R* is hydrogen or Ci _-6 alkyl; and a group -O-(CH ₂ )f -O- wherein f is from 1 to 3 and said group is bound to two points of substitution on the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ substituents so as to form a ring fused to the substituent.

In an embodiment, R ¹ is chosen to be a protecting group which can be easily removed after coupling, decarboxylation and reduction is complete but which is not displaced during these procedures. Any conventional protecting group which is capable of fulfilling this requirement can be used. In an embodiment, R ¹ is an optionally substituted group preferably selected from the group comprising: Ci_io alkyl, C-M _O alkyl aryl, and aryl. More preferably R ¹ is Ci-e alkyl or benzyl. Most preferably R ¹ is Ci _-6 alkyl.

In an embodiment R ² is an optionally substituted group selected from the group comprising: C- _M0 alkyl, Ci _-10 alkoxy and C ₃ - ₁₀ cycloalkyl. Preferably, R ² is C1-10 alkyl. More preferably, R ² is C ₂ - ₆ alkyl. Most preferably R ² is isopropyl.

In an embodiment, R ³ is an optionally substituted group selected from the group comprising: Ci _-I0 alkyl, Ci-i ₀ alkylaryl, aryl, -S-aryl, and het. More preferably R ³ is optionally substituted aryl, -S-aryl, or het. More preferably, R ³ is optionally substituted aryl or -S-aryl, and most preferably R ³ is optionally substituted phenyl or thiophenyl.

In an embodiment, R ⁴ is an optionally substituted group selected from the group comprising: hydrogen, Ci- _I0 alkyl, aryl and het, or R ⁴ is hydroxyl. Preferably R ⁴ is hydrogen.

In an embodiment, R ⁵ is an optionally substituted group selected from the group comprising: hydrogen, Ci-i ₀ alkyl, aryl, and het, or R ⁵ is hydroxyl. R ⁵ is preferably Ci-salkyl, such as ethyl and preferably methyl, or hydrogen. Preferably R ⁵ is hydrogen.

In an embodiment, R ⁶ is an optionally substituted group selected from the group comprising: hydrogen, Ci. ₁₀ alkyl and C ₃ - ₁ 0 cycloalkyl. Preferably R ⁶ is hydrogen.

In an embodiment, R ⁷ is selected from the group comprising: Ci_i ₀ alkyl; C2- ₁ Q alkynyl; C ₃ -10 cycloalkyl; aryl; C ₁ . ₁₀ alkylaryl; aryl C _h alky!; het; Ci_i _O alkyl het; and

het Ci_io alkyl. More preferably, R ⁷ is selected from the group comprising C-M _O alkyl, Ci _-10 alkylaryl, aryl and het. It is further preferred that R ⁷ is an optionally substituted aryl or het group, and still more preferably R ⁷ is optionally substituted aryl, most preferably phenyl. Most preferably, R ⁷ is 4-nitrophenyl.

In an embodiment, R ⁸ is chosen to be a leaving group which can be easily displaced in the base coupling reaction. In an embodiment, R ⁸ is an optionally substituted group selected from the group comprising: -C(O)OR**, -C(O)R** and -R**, where R** is C ₁ - ₁₀ , alkyl, C-M _O alkylaryl, and aryl, wherein each of the aforementioned groups may be optionally substituted by 1 to 5 substituents independently selected from the group comprising: halo, hydroxyl and CN.

In an embodiment, M is a Group IA metal. Preferably M is lithium, sodium or potassium, and most preferably sodium.

In an embodiment, P is a protecting group chosen to protect the amine functionality during synthesis of the compound of Formula (I), (IA) or (IB). Once the compound of Formula (I), (IA) or (IB) has been formed, the protecting group P can be removed using conventional deprotection procedures. The resulting deprotected amine can then be reacted with a compound R ⁷ SO ₂ X' where R ⁷ is as defined previously in relation to Formula (I) and X' is halo to form the compound of Formula (III) in which P is R ⁷ SO ₂ -.

In the base coupling reaction of compounds of Formula (IV) and (V) the deprotonation is usually performed under strong basic conditions. Any conventional strong base may be used. Suitable bases include alkyl lithium reagents.

It is recognised that the process of the present invention is set out as a series of steps and that these steps are described in a sequential manner, however this is not intended to limit the invention to any one specific mode of operation of these steps. The invention therefore includes operations wherein the steps are carried out in discrete sequential stages, operations wherein concurrent operation of the

steps occurs, and operations in which optional additional steps may occur between the steps. For example, in certain preferred embodiments, steps occur concurrently whereby a compound of Formula (IV) is reacted with a compound of Formula (V) to give a compound of Formula (III) and subsequent reaction to a compound of formula (II) occurs without isolation of the compound of Formula (II).

The synthetic procedures described herein may be adapted as appropriate to the reactants, reagents and other reaction parameters in a manner that will be evident to the skilled person by reference to standard textbooks such as

"Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (1999 or later editions), "March's Advanced Organic Chemistry - Reactions, Mechanisms and Structure", MB Smith, J. March, Wiley, (5th edition or later) "Advanced Organic Chemistry, Part B, Reactions and Synthesis", FA Carey, RJ Sundberg, Kluwer Academic/Plenum Publications, (2001 or later editions), "Organic Synthesis - The Disconnection Approach", S Warren (Wiley), (1982 or later editions), "Designing Organic Syntheses" S Warren (Wiley) (1983 or later editions), "Guidebook To Organic Synthesis" RK Mackie and DM Smith (Longman) (1982 or later editions), etc., and the references therein as a guideand to the examples provided hereinafter.

It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of certain compounds during operation of the process of the present invention. This may be achieved by conventional methods, for example as described in "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley & Sons lnc (1999), and references therein.

Alkyl groups that may be represented by C-M _O alkyl include linear and branched alkyl groups comprising up to 10 carbon atoms, and preferably from 1 to 6 carbon atoms. Examples of preferred alkyl groups include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, and t-butyl groups.

Alkenyl groups that may be represented by C2-10, alkenyl include one or more carbon - carbon double bonds. Preferably the group is a C _2-6 alkenyl group. Examples of alkenyl groups include vinyl, styryl and indenyl groups.

Aryl groups that may be represented by aryl may contain 1 ring or 2 or more fused rings and typically comprise up to 30 carbon atoms, particularly from 5 to 25 carbon atoms and preferably from 6 to 12 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracenyl and phenanthrenyl.

A heterocycle may be saturated, partially saturated or aromatic and contain one or more heteroatoms independently selected fron N, O and S. For example, the heterocyle may be a 5 to 6 membered saturated, partially saturated or aromatic heterocycle containing one to three heteroatoms independently selected from N, O and S. Examples of heterocyclic groups are tetrahydrofuranyl, thiolanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, sulfolanyl, dioxolanyl, dihydropyranyl, tetrahydropyranyl, piperidinyl, pyrazolinyl, pyrazolidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, azepinyl, oxazepinyl, thiazepinyl, thiazolinyl and diazapanyl. Examples of aromatic monoheterocyclic groups are pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazoles (such as 1 ,2,3 triazolyl and 1 ,2,4-triazolyl), oxadiazoles (such as 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl and 1-oxa~3,4-diazofyl), thiadiazoles (such as 1-thia-2,3-diazolyl, 1-thia-2,4- diazolyl, 1-thia-2,5-diazolyl and 1-thia-3,4-diazolyl), tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. Examples of bicyclic aromatic heterocyclic groups are benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl and isoquinolinyl.

Unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.

Halo means fluoro, chloro, bromo or iodo and is preferably fluoro or chloro.

Protecting groups that may be represented by P in any of the preceding formulae include optionally substituted silyl groups, such as optionally substituted tri- hydrocarbylsilyl groups, for example SiR'R"R'" wherein each R', R", and R'" is an optionally substituted hydrocarbyl group selected from the group comprising: Ci- io alkyl; Ci-io alkoxy; C ₂ -io alkenyl; C ₂ -io alkynyl; CM ₀ alkyl C _3-I0 cycloalkyl; and C ₃ - io cycloalkyl. Examples of substituted silyl groups include: SiMe ₃ , SiPh ₃ , SiEt ₃ , SiMe ₂ Ph; and optionally substituted phosphorous groups such as PO(R') ₂ and PO(OR') ₂ wherein each R' is an optionally substituted hydrocarbyl group as defined above. Examples of substituted phosphorus groups include: PO(Et) ₂ , PO(Ph) ₂ and PO(OEt) ₂ .

Preferred compounds of Formula (II), (III), (IV) and (V) have substituent groups corresponding to those preferred substituent groups listed above for the preferred compounds of Formula (I).

The base condensation reaction of the process of the present invention is preferably performed in a suitable solvent system. Suitable solvent systems include the use of single solvents and solvent mixtures, including multi phase solvent mixtures. Solvents include polar and non-polar solvents. Preferred polar solvents include polar, aprotic solvents, including nitriles, for example benzonitrile; and ethers, for example diethylether, t-butylmethylether and tetrahydrofuran. Preferred non-polar solvents include aliphatic and aromatic non- polar solvents for example hydrocarbons such as hexane, heptane, toluene and xylene. Most preferably the solvent system comprises an ether, preferably diethyl ether or more preferably tetrahydrofuran or mixtures thereof.

Bases that may be employed include strong bases. Preferably the base is a strong organometallic base. Preferred organometallic bases include alkyl and aryl alkali metals, for example methyl lithium, n-butyl lithium, s-butyl lithium and t- butyl lithium; alkyl and aryl grignard reagents, for example ethyl magnesium chloride, ethyl magnesium bromide, n-butyl magnesium chloride, n-butyl magnesium bromide, s-butyl magnesium chloride, s-butyl magnesium bromide, t-

butyl magnesium chloride and t-butyl magnesium bromide; amides of alkali and alkaline earth metals, for example lithium diisopropylamide, lithium hexamethyldisilylazide, lithium cyclohexylamide, magnesium bis(diisopropyl)amide, chloromagnesium isopropylamide and bromomagnesium isopropylamide; and metal alkoxides and hydrides for example potassium t- butoxide, sodium hydride, magnesium ethoxide and sodium ethoxide. The bases can be used singularly or in combination, optionally in a sequential manner. Preferably the base is lithium diisopropylamide.

The amount of base used is dependent on the nature of the compound Formula (V). When M is hydrogen 2 to 6 molar equivalents, preferably 2 to 3 equivalents, with respect to the compound of Formula (V) of base is used. When M is not hydrogen, 1 to 3 molar equivalents, preferably 1 to 1.5 equivalents, with respect to the compound of Formula (V) of base is used.

Optionally additives may be employed in the base condensation reaction. Additives that may be employed include additives known in the art that may be employed to deaggregate lithium, for example tetramethylethylenediamine.

The base condensation reaction of the process of the present invention is often carried out a temperature of from about -100°C to 20 ⁰ C. Commonly, the reaction is carried out a temperature of from -90°C to -20 ⁰ C, preferably from -85°C to - 60°C, and more preferably from -80 ⁰ C to -70 ⁰ C. Preferably, a compound of Formula (V) is reacted first with strong base at low temperature, most preferably - 80 ⁰ C to -70 ⁰ C, and then the resulting mixture is added to compound of Formula (IV). Optionally the temperature of the reaction mixture may be raised as the reaction progresses.

The decarboxylation step of the process of the present invention may be carried out by the addition of a proton source, for example aqueous solutions or acids, and/or by application of heat. Preferably a proton source, for example acetic acid, is added and the reaction mixture allowed to warm to -45 ⁰ C. When M is not a Group IA or HA metal, it is preferred that this group is first removed by for

example base hydrolysis.

Optionally the compound of formula (III) may be isolated prior to the reduction step. Isolation techniques include any techniques known in the art. Typically, water or aqueous solution, for example NaHCO ₃ solution, brine or mixtures thereof, is added to the reaction mixture at the end of the decarboxylation step, and the compound of formula (III) is obtained by solvent extraction, for example by using an ester solvent such as ethyl acetate.

Optionally, additional chiral separation, crystallization or polishing steps may be included, prior to the reduction step.

Reducing agents that may be employed in the reducing step include reducing agents which are known in the art to be useful in the reduction of ketones, for example metal hydrides, for example NaBH ₄ , LiBH ₄ , or LiAIH ₄ , bio-reduction systems, for example by employing ketone reductase enzymes or whole cells systems comprising ketone reductases, asymmetric hydrogenation system, for example hydrogen and chiral metal catalysts such as DuPHOS™. Also specifically included and specifically intended to form part of the subject matter of the present invention are catalytic transfer hydrogenation systems and processes including those systems and processes disclosed in International patent application publication numbers WO97/20789, WO98/42643, and WO02/44111. Hence the reader is directed towards each of those disclosures and the catalysts described therein as they have utility in the reduction step of the present invention. These catalysts and systems are specifically incorporated herein by reference.

The reduction step of the process is preferably performed in a suitable solvent system. Solvents systems are selected so as to be compatible with the reducing agents employed and are known in the art. Preferred solvents are those that do not adversely impact on the effectiveness of the reducing agent. Suitable solvent systems include the use of single solvents and solvent mixtures, including multiphasic solvent mixtures. Solvents include polar and non-polar solvents.

Preferred polar solvents include polar, aprotic solvents, including halocarbons, for example dichloromethane, chloroform and 1 ,2-dichloroethane; nitriles, for example acetonitrile; and ethers, for example diethylether and tetrahydrofuran. Preferred non-polar solvents include aliphatic and aromatic non-polar solvents for example hydrocarbons such as hexanes, toluene and xylene.

In a preferred embodiment, catalytic transfer hydrogenation systems and processes are employed in the reduction step. Preferably this step is performed under chiral conditions so as to lead to preferential or exclusive formation of one stereoisomeric product.

When catalytic transfer hydrogenation systems and processes are employed in the reduction step, preferably the systems and processes employ a transfer hydrogenation catalyst and a hydrogen donor.

Preferably the transfer hydrogenation catalyst is a transfer hydrogenation catalyst of general Formula (A):

Y Wi 9

Formula (A)

wherein:

R ¹⁹ represents a neutral optionally substituted hydrocarbyl or an optionally substituted cyclopentadienyl ligand;

A represents -NR ⁹ -, -NR ¹⁰ -, -NHR ⁹ , -NR ⁹ R ¹⁰ Or -NR ¹⁰ R ¹¹ where R ⁹ is H, C(O)R ¹¹ , SO ₂ R ¹¹ , C(O)NR ¹¹ R ¹⁵ , C(S)NR ¹¹ R ¹⁵ , C(=NR ¹⁵ )SR ¹⁶ or C(=NR ¹⁵ )OR ¹⁶ , R ¹⁰ and R ¹¹ each independently represents an optionally substituted hydrocarbyl or an optionally substituted heterocyclyl group, and R ¹⁵ and R ¹⁶ are each independently hydrogen or a group as defined for R ¹¹ ;

B represents -O-, -OH, OR ¹² , -S-, -SH, SR ¹² , -NR ¹² -, -NR ¹³ -, -NHR ¹³ , -NR ¹² R ¹³ , -NR ¹² R ¹⁴ , -PR ¹² - or -PR ¹² R ¹⁴ where R ¹³ is H, C(O)R ¹⁴ , SO ₂ R ¹⁴ , C(O)NR ¹⁴ R ¹⁷ , C(S)NR ¹⁴ R ¹⁷ , C(=NR ¹⁷ )SR ¹⁸ or C(=NR ¹⁷ )OR ¹⁸ , R ¹² and R ¹⁴ each independently represents an optionally substituted hydrocarbyl or an optionally substituted heterocyclyl group, and R ¹⁷ and R ¹⁸ are each independently hydrogen or a group as defined for R ¹⁴ ;

E represents a linking group;

M' represents a metal capable of catalysing transfer hydrogenation; and

Y represents an anionic group, a basic Iigand or a vacant site;

provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom.

The catalytic species is believed to be substantially as represented in the above formula. It may be introduced on a solid support.

Optionally substituted hydrocarbyl groups represented by R ^10'12 or R ^14'18 include alkyl, alkenyl, alkynyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups.

Alkyl groups which may be represented by R ^10"12 or R ^14"18 include linear and branched alkyl groups comprising 1 to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings. Examples of alkyl groups which may be represented by R ^10"12 or R ^14"18 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups.

Alkenyl groups which may be represented by one or more of R ^10'12 or R ¹⁴ - ¹⁸

include C ₂ - ₂₀ , and preferably C ₂ -6 alkenyl groups. One or more carbon - carbon double bonds may be present. The alkenyl group may carry one or more substituents, particularly phenyl substituents.

Alkynyl groups which may be represented by one or more of R ^10"12 or R ^14'18 include C2- ₂ 0, and preferably C ₂ -io alkynyl groups. One or more carbon - carbon triple bonds may be present. The alkynyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkynyl groups include ethynyl, propyl and phenylethynyl groups.

Aryl groups which may be represented by one or more of R ^10"12 or R ^14"18 may contain 1 ring or 2 or more fused or bridged rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups which may be represented by R ^10"12 or R ^14"18 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups.

Heterocyclic groups which may be represented by one or more of R ^10'12 or R ^14"18 independently include aromatic, saturated and partially unsaturated ring systems and may comprise 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. The heterocyclic group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P. Examples of heterocyclic groups which may be represented by R ^10"12 or R ^14"18 include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazolyl and triazolyl groups.

When any of R ^10"12 or R ^14"18 is a substituted hydrocarbyl or heterocyclic group, the substituent(s) should be such so as not to adversely affect the rate or stereoselectivity of the reaction. Optional substituents include halogen, cyano, nitro, hydroxy, amino, imino, thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carboxy, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R ^10"12 or R ¹⁴ - ¹⁸ above. One or

more substituents may be present. Examples of R ^10"12 or R ^14"18 groups having more than one substituent present include -CF ₃ , -CCI ₃ , -CF ₂ H and -C ₂ F ₅ . R ^10"12 or R ¹⁴ - ¹⁸ may each contain one or more chiral centres.

The neutral optionally substituted hydrocarbyl ligand which may be represented by R ¹⁹ includes optionally substituted aryl and alkenyl ligands.

Optionally substituted aryl ligands which may be represented by R ¹⁹ may contain 1 ring or 2 or more fused rings which include cycloalkyl, aryl or heterocyclic rings. Preferably, the ligand comprises a 6 membered aromatic ring. The ring or rings of the aryl ligand are often substituted with hydrocarbyl groups. The substitution pattern and the number of substituents will vary and may be influenced by the number of rings present, but often from 1 to 6 hydrocarbyl substituent groups are present, preferably 2, 3 or 6 hydrocarbyl groups and more preferably 6 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl, iso- propyl, menthyl, neomenthyl and phenyl. Particularly when the aryl ligand is a single ring, the ligand is preferably benzene or a substituted benzene. When the ligand is a hydrocarbyl ligand substituted with halogens, preferably it is a polyhalogenated benzene such as hexachlorobenzene or hexafluorobenzne. When the hydrocarbyl substitutents contain enantiomeric and/or diastereomeric centres, it is preferred that the enantiomerically and/or diastereomerically purified forms of these are used. Benzene, p-cymyl, mesitylene and hexamethylbenzene are especially preferred ligands.

Optionally substituted alkenyl ligands which may be represented by R ¹⁹ include C2- ₃₀ , and preferably C _6- i ₂ , alkenes or cycloalkenes with preferably two or more carbon-carbon double bonds, preferably only two carbon-carbon double bonds. The carbon-carbon double bonds may optionally be conjugated to other unsaturated systems which may be present, but are preferably conjugated to each other. The alkenes or cycloalkenes may be substituted preferably with hydrocarbyl substituents. When the alkene has only one double bond, the optionally substituted alkenyl ligand may comprise two separate alkenes. Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl and phenyl.

Examples of optionally substituted alkenyl ligands include cyclo-octa-1 ,5-diene and 2,5-norbornadiene. Cyclo-octa-1 ,5-diene is especially preferred.

Optionally substituted cyclopentadienyl groups which may be represented by R ¹⁹ include cyclopentadienyl groups capable of eta-5 bonding. The cyclopentadienyl group is often substituted with from 1 to 5 hydrocarbyl groups, preferably with 3 to 5 hydrocarbyl groups and more preferably with 5 hydrocarbyl groups.

Preferred hydrocarbyl substituents include methyl, ethyl and phenyl. When the hydrocarbyl substitutents contain enantiomeric and/or diastereomeric centres, it is preferred that the enantiomerically and/or diastereomerically purified forms of these are used. Examples of optionally substituted cyclopentadienyl groups include cyclopentadienyl, pentamethyl-cyclopentadienyl, pentaphenylcyclopentadienyl, tetraphenylcyclopentadienyl, ethyltetramethylpentadienyl, menthyltetraphenylcyclopentadienyl, neomenthyl- tetraphenylcyclopentadienyl, menthylcyclopentadienyl, neomenthylcyclopentadienyl, tetrahydroindenyl, menthyltetrahydroindenyl and neomenthyltetrahydroindenyl groups. Pentamethylcyclopentadienyl is especially preferred.

When either A or B is an amide group represented by -NR ⁹ -, -NHR ⁹ , NR ⁹ R ¹⁰ ,

-NR ¹³ -, -NHR ¹³ or NR ¹² R ¹³ wherein R ¹⁰ and R ¹² are as hereinbefore defined, and where R ⁹ or R ¹³ is an acyl group represented by -C(O)R ¹¹ or -C(O)R ¹⁴ , R ¹¹ and R ¹⁴ independently are often linear or branched Ci_ ₇ alkyl, C-i-s-cycloalkyl or aryl, for example phenyl. Examples of acyl groups which may be represented by R ⁹ or R ¹³ include benzoyl, acetyl and halogenoacetyl, especially trifluoroacetyl, groups.

When either A or B is present as a sulphonamide group represented by -NR ⁹ -, -NHR ⁹ , NR ⁹ R ¹⁰ , -NR ¹³ -, -NHR ¹³ or NR ¹² R ¹³ wherein R ¹⁰ and R ¹² are as hereinbefore defined, and where R ⁹ or R ¹³ is a sulphonyl group represented by - S(O) ₂ R ¹¹ or -S(O) ₂ R ¹⁴ , R ¹¹ and R ¹⁴ independently are often linear or branched Ci_ ₈ alkyl, Ci _-8 cycloalkyl or aryl, for example phenyl, tolyl. Preferred sulphonyl groups which may be represented by R ⁹ or R ¹³ include methanesulphonyl, trifluoromethanesulphonyl and especially p-toluenesulphonyl groups and

naphthylsulphonyl groups.

When either of A or B is present as a group represented by -NR ⁹ -, -NHR ⁹ ,

NR ⁹ R ¹⁰ , -NR ¹³ -, -NHR ¹³ or NR ¹² R ¹³ wherein R ¹⁰ and R ¹² are as hereinbefore defined, and where R ⁹ or R ¹³ is a group represented by C(O)NR ¹¹ R ¹⁵ ,

C(S)NR ¹¹ R ¹⁵ , C(=NR ¹⁵ )SR ¹⁶ , C(=NR ¹⁵ )OR ¹⁶ , C(O)NR ¹⁴ R ¹¹⁷ , C(S)NR ¹⁴ R ¹⁷ ,

C(=NR ¹⁷ )SR ¹⁸ or C(=NR ¹⁷ )OR ¹⁸ , R ¹¹ and R ¹⁴ independently are often linear or branched Ci. ₈ alkyl, such as methyl, ethyl, isopropyl, C-i-scycloalkyl or aryl, for example phenyl, groups and R ^15"18 are often each independently hydrogen or linear or branched Ci_ ₈ alkyl, such as methyl, ethyl, isopropyl, C-ι_ ₈ cycloalkyl or aryl, for example phenyl, groups.

When B is present as a group represented by -OR ¹² , -SR ¹² , -PR ¹² - or -PR ¹² R ¹⁴ R ¹² and R ¹⁴ independently are often linear or branched Ci _-8 alkyl, such as methyl ethyl, isopropyl, C^cycloalkyl or aryl, for example phenyl.

It will be recognised that the precise nature of A and B will be determined by whether A and/or B are formally bonded to the metal or are coordinated to the metal via a lone pair of electrons.

The groups A and B are connected by a linking group E. The linking group E achieves a suitable conformation of A and B so as to allow both A and B to bond or coordinate to the metal, M'. A and B are commonly linked through 2, 3 or 4 atoms. The atoms in E linking A and B may carry one or more substituents. The atoms in E, especially the atoms alpha to A or B, may be linked to A and B, in such a way as to form a heterocyclic ring, preferably a saturated ring, and particularly a 5, 6 or 7-membered ring. Such a ring may be fused to one or more other rings. Often the atoms linking A and B will be carbon atoms. Preferably, one or more of the carbon atoms linking A and B will carry substituents in addition to A or B. Substituent groups include those which may substitute R ^10"12 or R ^14"18 as defined above. Advantageously, any such substituent groups are selected to be groups which do not coordinate with the metal, M'. Preferred substituents include halogen, cyano, nitro, sulphonyl, hydrocarbyl,

perhalogenated hydrocarbyl and heterocyclyl groups as defined above. Most preferred substituents are C _1-6 alkyl groups, and phenyl groups. Most preferably, A and B are linked by two carbon atoms, and especially an optionally substituted ethyl moiety. When A and B are linked by two carbon atoms, the two carbon atoms linking A and B may comprise part of an aromatic or aliphatic cyclic group, particularly a 5, 6 or 7-membered ring. Such a ring may be fused to one or more other such rings. Particularly preferred are embodiments in which E represents a 2 carbon atom separation and one or both of the carbon atoms carries an optionally substituted aryl group as defined above or E represents a 2 carbon atom separation which comprises a cyclopentane or cyclohexane ring, optionally fused to a phenyl ring.

E preferably comprises part of a compound having at least one stereospecific centre. Where any or all of the 2, 3 or 4 atoms linking A and B are substituted so as to define at least one stereospecific centre on one or more of these atoms, it is preferred that at least one of the stereospecific centres be located at the atom adjacent to either group A or B. When at least one such stereospecific centre is present, it is advantageously present in an enantiomerically purified state.

When B represents -O- or -OH, and the adjacent atom in E is carbon, it is preferred that B does not form part of a carboxylic group.

Compounds which may be represented by A-E-B, or from which A-E-B may be derived by deprotonation, are often aminoalcohols, including 4-aminoalkan-1-ols, 1-aminoalkan-4-ols, 3-aminoalkan-1-ols, 1-aminoalkan-3-ols, and especially

2-aminoalkan-1-ols, 1-aminoalkan-2-ols, 3-aminoalkan-2-ols and 2-aminoalkan-

3-ols, and particularly 2-aminoethanols or 3-aminopropanols, or are diamines, including

1 ,4-diaminoalkanes, 1 ,3-diaminoalkanes, especially 1,2- or 2,3- diaminoalkanes and particularly ethylenediamines. Further aminoalcohols that may be represented by A-E-B are 2-aminocyclopentanols and 2-aminocyclohexanols, preferably fused to a phenyl ring. Further diamines that may be represented by A-E-B are 1 ,2-diaminocyclopentanes and 1 ,2-diaminocycIohexanes, preferably

fused to a phenyl ring. The amino groups may advantageously be N-tosylated. When a diamine is represented by A-E-B, preferably at least one amino group is N-tosylated. The aminoalcohols or diamines are advantageously substituted, especially on the linking group, E, by at least one alkyl group, such as a C-1-4- alkyl, and particularly a methyl, group or at least one aryl group, particularly a phenyl group.

Specific examples of compounds which can be represented by A-E-B and the protonated equivalents from which they may be derived are:

Preferably, the enantiomerically and/or diastereomerically purified forms of these are used. Examples include (1S,2R)-(+)-norephedrine, (1R,2S)-(+)-cis-1-amino- 2-indanol, (1S,2R)-2-amino-1 ,2-diphenylethanol, (1S,2R)-(-)-cis-1-amino-2- indanol, (1R,2S)-(-)-norephedrine, (S)-(+)-2-amino-1-phenylethanol, (1R,2S)-2- amino-1 ,2-diphenylethanol, N-tosyl-(1 R,2R)-1 ,2-diphenylethylenediamine, N- tosyl-(1 S,2S)-1 ,2-diphenylethylenediamine, (1 R,2S)-cis-1 ,2-indandiamine,

(1S,2R)-cis-1,2-indandiamine, (R)-(-)-2-pyrrolidinemethanol and (S)-(+)-2- pyrrolidinemethanol.

Metals which may be represented by M' include metals which are capable of catalysing transfer hydrogenation. Preferred metals include transition metals, more preferably the metals in Group VIII of the Periodic Table, especially ruthenium, rhodium or iridium. When the metal is ruthenium it is preferably present in valence state II. When the metal is rhodium or iridium it is preferably

present in valence state I when R ¹⁹ is a neutral optionally substituted hydrocarbyl or a neutral optionally substituted perhalogenated hydrocarbyl ligand, and pprreeffeerraabbllyy pprreesseenntt iinn vvalence state III when R ¹⁹ is an optionally substituted cyclopentadienyl ligand.

It is preferred that M', the metal, is rhodium present in valence state III and R ¹⁹ is an optionally substituted cyclopentadienyl ligand.

Anionic groups which may be represented by Y include hydride, hydroxy, hydrocarbyloxy, hydrocarbylamino and halogen groups. Preferably when a halogen is represented by Y, the halogen is chloride. When a hydrocarbyloxy or hydrocarbylamino group is represented by Y, the group may be derived from the deprotonation of the hydrogen donor utilised in the reaction.

Basic ligands which may be represented by Y include water, C _1-4 alcohols, Ci _-8 primary or secondary amines, or the hydrogen donor which is present in the reaction system. A preferred basic ligand represented by Y is water.

Most preferably, A-E-B, R ¹⁹ and Y are chosen so that the catalyst is chiral. When such is the case, an enantiomerically and/or diastereomerically purified form is preferably employed. Such catalysts are most advantageously employed in asymmetric transfer hydrogenation processes. In many embodiments, the chirality of the catalyst is derived from the nature of A-E-B.

Particularly preferred transfer hydrogenation catalysts are those Ru, Rh or Ir catalysts of the type described in WO97/20789, WO98/42643, and WO02/44111 which comprise an optionally substituted diamine ligand, for example an optionally substituted ethylene diamine ligand, wherein at least one nitrogen atom of the optionally substituted diamine ligand is substituted with a group containing a chiral centre, and a neutral aromatic ligand, for example p-cymene or optionally substituted cyclopentadiene ligands.

Preferred catalysts are of Formula B(i-ii), C(i-iv), D(i-ii) and E(i-iv):

B(D B(ii)

C(O C(ii)

C(iii) COv)

D(O D(ii)

E(O E(N)

E(iii) ECv)

Examples of these especially preferred catalysts include that catalysts obtained by reacting rhodium pentamethylcyclopentadiene dichloride dimer with N- sulphonyl-diphenylethylenediamines, for example N-p-tolylsulphonyl-(S,S)- diphenylethylenediamine, under the conditions described in Example 6 of WO98/42643 to give a catalyst of Formula

Cp* = Pentamethylcyclopeπtadiene

The preferred catalyst may be prepared in-situ preferably by combining a chiral bidentate nitrogen ligand with a Rh(III) metal complex containing a substituted cyclopentadienyl ligand or a Ru(II) metal complex containing a substituted phenyl ligand. Preferably a solvent is present in this operation. The solvent used may be any solvent which does not adversely effect the formation of the catalyst.

These solvents include acetonitrile, ethylacetate, toluene, methanol, tetrahydrofuran, ethylmethyl ketone and dimethyformamide. Preferably the solvent is acetonitrile or dimethylformamide.

When catalytic transfer hydrogenation processes are employed in the reduction step, it is preferred that a hydrogen donor is present. Preferred hydrogen donors include hydrogen, primary and secondary alcohols, primary and secondary amines, carboxylic acids and their esters and amine salts, readily dehydrogenatable hydrocarbons, clean reducing agents, and any combination thereof.

Primary and secondary alcohols which may be employed in the preferred embodiment of the reduction step as hydrogen donors comprise commonly from

1 to 10 carbon atoms, preferably from 2 to 7 carbon atoms, and more preferably

3 or 4 carbon atoms. Examples of primary and secondary alcohols which may be represented as hydrogen donors include methanol, ethanol, propan-1-ol, propan-

2-ol, butan-1-ol, butan-2-ol, cyclopentanol, cyclohexanol, benzylalcohol, and menthol, especially propan-2-ol and butan-2-ol.

Primary and secondary amines which may be employed in the preferred embodiment of the reduction step as hydrogen donors comprise commonly from

1 to 20 carbon atoms, preferably from 2 to 14 carbon atoms, and more preferably 3 or 8 carbon atoms. Examples of primary and secondary amines which may act as hydrogen donors include ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, hexylamine, diethylamine, dipropylamine, di- isopropylamine, dibutylamine, di-isobutylamine, dihexylamine, benzylamine, dibenzylamine and piperidine. When the hydrogen donor is an amine, primary amines are preferred, especially primary amines comprising a secondary alkyl group, particularly isopropylamine and isobutylamine.

Carboxylic acids and their esters which in a preferred embodiment of the reduction step may act as hydrogen donors comprise commonly from 1 to 10 carbon atoms, preferably from 1 to 3 carbon atoms. In certain embodiments, the carboxylic acid is advantageously a beta-hydroxy-carboxylic acid. Esters may be derived from the carboxylic acid and a C-M _O alcohol. Examples of carboxylic acids which may be employed as hydrogen donors include formic acid, lactic acid, ascorbic acid and mandelic acid, especially formic acid.

In certain preferred embodiments, when a carboxylic acid is employed as hydrogen donor, at least some of the carboxylic acid is preferably present as salt, preferably an amine, ammonium or metal salt. Preferably, when a metal salt is present the metal is selected from the alkali or alkaline earth metals of the periodic table, and more preferably is selected from the group I elements, such as lithium, sodium or potassium. Amines which may be used to form such salts include; primary, secondary and tertiary amines which comprise from 1 to 20 carbon atoms. Cyclic amines, both aromatic and non-aromatic, may also be used. Tertiary amines, especially trialkylamines, are preferred. Examples of amines which may be used to form salts include; trimethylamine, triethylamine, di-isopropylethylamine and pyridine. The most preferred amine is triethylamine.

When at least some of the carboxylic acid is present as an amine salt, particularly when a mixture of formic acid and triethylamine is employed, the mole ratio of acid to amine is between 1 :1 and 50:1 and preferably between 1 :1 and 10:1 , and most preferably about 5:2. When at least some of the carboxylic acid

is present as a metal salt, particularly when a mixture of formic acid and a group I metal salt is employed, the mole ratio of acid to metal ions present is between 1:1 and 50:1 and preferably between 1 :1 and 10:1, and most preferably about 2:1. The ratios of acid to salts may be maintained during the course of the reaction by the addition of either component, but usually by the addition of the carboxylic acid.

Readily dehydrogenatable hydrocarbons which may be employed in the reduction step as hydrogen donors comprise hydrocarbons which have a propensity to aromatise or hydrocarbons which have a propensity to form highly conjugated systems. Examples of readily dehydrogenatable hydrocarbons which may be employed by as hydrogen donors include cyclohexadiene, cyclohexene, tetralin, dihydrofuran and terpenes.

Clean reducing agents able to act as hydrogen donors comprise reducing agents with a high reduction potential, particularly those having a reduction potential relative to the standard hydrogen electrode of greater than about -0.1 eV, often greater than about -0.5eV, and preferably greater than about -1eV. Examples of suitable clean reducing agents include hydrazine and hydroxylamine.

Preferred hydrogen donors are propan-2-ol, butan-2-ol, triethylammonium formate and a mixture of triethylammonium formate and formic acid.

The most preferred transfer hydrogenation processes employ triethylamine- formic acid as hydrogen source.

When catalytic transfer hydrogenation processes are employed the reduction step, preferably the process is performed in a suitable system. Suitable solvent systems include nitriles, for example acetonitrile; hydrocarbons, for example toluene; ethers, for example methyl t-butyl ether; alcohols; halogenated hydrocarbons or, conveniently, the hydrogen donor when the hydrogen donor is liquid at the reaction temperature, particularly when the hydrogen donor is a primary or secondary alcohol or a primary or secondary amine. Although it is

possible to operate in the substantial absence of water, the use of water and an organic solvent to operate the process as a multi-phase system is preferred. Such multi-phase systems may ameliorate the production of hydrogen.

The multi-phase system preferably comprises two or more liquid phases. More preferably the multi-phase system is a two phase system comprising a water immiscible solvent phase and an aqueous or water phase.

When a two phase system comprising a water immiscible solvent phase and an aqueous or water phase is employed, the water immiscible solvent phase may be dispersed in the continuous aqueous or water phase or the aqueous or water phase may be dispersed in the continuous water immiscible solvent phase.

Preferably, the transfer hydrogenation catalyst is soluble in the water immiscible solvent phase. Preferably the hydrogen donor is soluble in the aqueous or water phase.

Preferred transfer hydrogenation catalysts are those transfer hydrogenation catalysts described herein before above which are soluble in water immiscible solvents.

Preferred transfer hydrogenation catalysts which are soluble in water immiscible solvents are those optionally substituted transfer hydrogenation catalysts which do not comprise substitutents that confer water solubility. For example, substitutents that confer water solubility include sulphonic acid groups or salts thereof.

Preferred water immiscible solvents include those polar and non-polar organic solvents described herein before above which are partially or fully water immiscible. Preferred water immiscible solvents include t-butyl acetate, THF. Dichloromethane is a highly preferred water immiscible solvent.

Optionally a phase transfer catalyst may be present. Surprisingly it has been

found that the use of phase transfer catalysts may increase reaction rates. Examples of phase transfer catalysts include quaternary ammonium salts such as halides and sulphates, for example (Bu ₄ NT) ₂ SO ₄ ^2' . The use of phase transfer catalysts is preferred.

Optionally the compound of Formula (I) may be isolated following the reduction step by any techniques known in the art. Typically, water or aqueous solution, for example NaHCO ₃ solution, brine or mixtures thereof, is added to the reaction mixture at the end of the reduction step, and the compound of Formula (I) is obtained by solvent extraction, for example by using an ester solvent such as ethyl acetate.

Optionally, additional diastereomer separation, crystallization or polishing steps may be included, following the reduction step.

The compounds of Formula (II), (III), (Ha) and (Ilia) are valuable intermediates useful in the preparation of compounds of Formula (I), (IA) and (IB) and form further aspects of the present invention.

The invention will now be illustrated by the following Examples

Example 1 - Preparation of Compound of Formula (II)

The compound of formula (II) may be prepared as follows. 1-6 molar equivalents of strong base, such as butyl lithium, lithium diisopropylamide or butylmagnesium chloride, or magnesium, or a combination of one or more of these sequentially optionally in the presence of an inorganic magnesium salt, such as magnesium chloride, is added with stirring to a solution of a compound of formula (V) [see Lawrence J. MacPherson et. al., J. Med. Chem., 1997, 40, 2525-2532 and Elena Carceller et. al. J. Med. Chem., 2001, 44, 18, 3001-3013] in a solvent, such as THF, under an inert atmosphere at a temperature of between -100 ⁰ C and 2O ⁰ C. This solution may then be added to a solution of compound of formula (IV), such

as BocPheOMe (Boc-L-phenylalanine methyl ester available from Aldrich™), in a solvent, such as THF, over a period of 0.5 to 2 h. A solution of aqueous acid, such as HCI, would be added to the mixture and the solution stirred for a further 0.5 to 2 h. The organic phase would be separated and the aqueous phase extracted with a solvent such as ethyl acetate or diethyl ether. The combined organic extracts would be sequentially washed with one or more aqueous solutions, e.g. water, saturated aqueous sodium hydrogen carbonate solution, sodium chloride solution, dried with MgSO ₄ or Na2SO ₄ and then concentrated under reduced pressure.

Example 2 - Reduction of a Compound of Formula (II) under bi-phasic conditions

Method:

A solution of ketone (1 mmol) in dichloromethane (2ml_) was added to a solution of ligand (~0.010 mmol), metal (~0.005 mmol), sodium formate (0.006 mmol) in water (5 ml_) at room temperature. The reaction mixture was stirred vigorously at room temperature and monitored by LC.

Analysis:

The reaction mixture was monitored by LC using a Phenomenex™ Luna C18 (2) column, 250 mm x 4.6 mm, 5μm, serial number (394173) and a mixture of water (containing 0.1% TFA) and acetonitrile (containing 0.1% TFA) as a mobile phase. The run was carried out with a gradient. The retention times were as follow 12.3 min (product alcohol, shown above), 13.8 min (the other diastereoisomer of the alcohol) and 18.7 min (ketone).

Example 2a:

(S ₁ R ₁ R)-CSDPEN (4.9 mg), [RuCI ₂ (p-cymene)] ₂ (2.7 mg), NaHCO ₂ (0.41 g) and the ketone (0.49 g) provided the product alcohol in 88% conversion ^1" and 85% d.e. after 29h. By LC area, 78% of the mixture was the product alcohol, 6% for the diastereoisomer, 11% for the ketone and 5% for impurities. fthe conversion was calculated based on the LC area of product and starting material.

Example 2b: (S ₁ S ₁ S)-CSDPEN (4.1 mg), [RuCI ₂ (p-cymene)] ₂ (2.8 mg), NaHCO ₂ (0.42 g) and the ketone (0.49 g) provided the diastereoisomer of the product in 100% conversion* and 65% d.e. after 26h. By LC area, 14% of the mixture was the product alcohol, 74% for the diastereoisomer and 12% for impurities. fthe conversion was calculated based on the LC area of product and starting material.

Example 2c:

(S ₁ R ₁ R)-CSDPEN (4.3 mg), [RhCl ₂ Cp ^* ] ₂ (3.0 mg), NaHCO ₂ (0.40 g) and the ketone (0.50 g) provided the diastereoisomer of the product in 75% conversion* and 86% d.e. after 26h. By LC area, 4% of the mixture was the product alcohol, 60% for the diastereoisomer, 22% for the ketone and 14% for impurities. fthe conversion was calculated based on the LC area of product and starting material.

Example 3 - Reduction of a Compound of Formula (II) using TEAF.

Method:

A mixture of Ligand (~0.016 mmol), metal (~0.008 mmol) in TEAF (4 ml_) was stirred under nitrogen at room temperature for 30 min. A solution of ketone (1 mmol) in DMF (4 ml_) was added and the mixture was stirred at room temperature. The reaction was monitored by LC.

Analysis:

The reaction mixture was monitored by LC using a Phenomenex™ Luna C18 (2) column, 250 mm x 4.6 mm, 5Dm, serial number (394173) and a mixture of water (containing 0.1 % TFA) and acetonitrile (containing 0.1% TFA) as a mobile phase. The run was carried out with a gradient. The retention times were as follow 12.3 min (product alcohol shown above), 13.8 min (diastereoisomer of the product alcohol) and 18.7 min (ketone).

Example 3a:

Using (S ₁ R ₁ R)-CSDPEN (7.5 mg), [RuCI ₂ (p-cymene)] ₂ (5.4 mg) and the ketone (0.5121 g) provided the product alcohol in 35% d.e. after 24h. By LC area 43% of the mixture was accounted for the product, 20.6% for the diastereoisomer, 21.4% for the ketone and 15% for impurities.

Example 3b:

Using (R ₁ S ₁ S)-CSDPEN (6.2 mg), [RhCI ₂ Cp ^* ] ₂ (4.8 mg) and the ketone (0.50 g) provided the product alcohol in 71% d.e. after 24h. By LC area 15% of the mixture was accounted for the product, 3% for the diastereoisomer, 46% for the ketone and 37% for impurities.

Independent preparation of compound of Formula (II):

Procedure:

Using a separating funnel, dichloromethane (500 mL) was shaken with water (30 ml_) and then separated from the aqueous layer. The alcohol (4.70 g, 9.01 mmol) was dissolved in the water-saturated dichloromethane (250 mL) at room temperature. Dess-Martin periodinane (15.71 g, 34.87 mmol) was added by portion and the milky suspension was stirred for 1 h. By TLC, the reaction was complete (Silica gel, hexanes:ethylacetate, 2:1, v/v, Rf = 0.71). The mixture was concentrated in vacuo down to a third of the original volume. The mixture was taken up in diethyl ether (400 mL) and washed with a 1 :1 mixture of 10% aqueous Na ₂ S ₂ O ₃ and saturated aqueous NaHCO ₃ (2 x 400 mL). The organic solution was washed with water (400 mL), brine (400 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to dryness to afford 5.0 g of white solid (93% yield).

Analysis:

The product was analysed by LC using a Phenomenex™ Luna C18 (2) column, 250 mm x 4.6 mm, 5Dm, serial number (394173) and a mixture of water

(containing 0.1% TFA) and acetonitrile (containing 0.1% TFA) as a mobile phase.

The run was carried out with a gradient. The retention time of the product was

19.0 min.

&(ppm. CDCI ₃ ) 0.80-0.84 (6H ₁ m, (CH ₃ ) ₂ CH), 1.43 (9H, s, (CH ₃ ) ₃ C), 1.53-1.70 (1 H, m, CH(CHs) ₂ ), 2.82-3.03 (4H, m, 2 *CH ₂ ), 4.02 (1H, apparent d, J 19.6,

CHH), 4.30-4.38 (2H, CHH, NHCHCO), 4.90 (1H, d, J 6.1, NH), 7.08-7.39 (5H, m, H aromatic), 7.89 (2H, d, J 9.0, H aromatic), 8.29 (2H, d, J 9.0, H aromatic);

&(ppm. CDCk) 20.1 , 26.8, 28.6, 37.5, 55.3, 55.6, 58.3, 81.1, 124.3, 127.9,

129.0, 129.4, 129.5, 135.8, 146.3, 150.2, 155.7, 204.6 v _ma y(KBrVcm ^'1 3359, 2980, 2956, 2935, 2870, 1743, 1704, 1690, 1607, 1538,

1523